rs1554082512

Variant names:

• chr5-148433635-G-A
• rs1554082512
• NM_205836.3:c.2755G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_205836.3(FBXO38):​c.2755G>A​(p.Val919Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXO38 NM_205836.3 missense, splice_region
• Scores: Splicing: ADA: 0.9983
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48
• Publications: 0 publications found

Genes affected

FBXO38 (HGNC:28844): (F-box protein 38) This gene encodes a large protein that contains an F-box domain and may participate in protein ubiquitination. The encoded protein is a transcriptional co-activator of Krueppel-like factor 7 (Klf7). A heterozygous mutation in this gene was found in individuals with autosomal dominant distal hereditary motor neuronopathy type IID. There is a pseudogene for this gene on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

FBXO38 Gene-Disease associations (from GenCC):

• neuronopathy, distal hereditary motor, type 2D

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• distal hereditary motor neuropathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• distal hereditary motor neuropathy type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO38	NM_205836.3	c.2755G>A	p.Val919Ile	missense_variant, splice_region_variant	Exon 17 of 22	ENST00000340253.10	NP_995308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO38	ENST00000340253.10	c.2755G>A	p.Val919Ile	missense_variant, splice_region_variant	Exon 17 of 22	5	NM_205836.3	ENSP00000342023.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Distal hereditary motor neuropathy type 2 Uncertain:1

Jun 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in one or more individuals who were not affected with FBXO38-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 541012). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 844 of the FBXO38 protein (p.Val844Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;T;.;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L;.;.
PhyloP100		5.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.54	N;N;N;N
REVEL	Benign	0.043
Sift	Pathogenic	0.0	D;T;T;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.0040	B;P;B;B
Vest4		0.19
MutPred		0.27		.;Loss of catalytic residue at V919 (P = 0.0217);.;.;
MVP		0.16
MPC		1.6
ClinPred		0.75	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.21
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554082512; hg19: chr5-147813198;